On the Synthesis of Zwitterionic Heteropolycyclic Pyrazoles by a Three

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On the Synthesis of Zwitterionic Heteropolycyclic Pyrazoles by a Three-Component Reaction. Some Mechanistic Considerations’ Heinrich Wamhoff,**tChristian Bamberg,t.2Stefan Herrmann,? and Martin Niegerl: Institut fiir Organische Chemie und Bwchemie and Institut f i r Anorganische Chemie der Universitat, Gerhard-Domagk-Str. 1,D-53121 Bonn, Germany Received February 8, 1994@

The novel three-component reaction involving a heterocyclic iminophosphorane,an isocyanate, and a hetarene component is applied to an aromatic pyrazole iminophosphorane 1 and to an analogous pyrazolone derivative 13. The hitherto unknown zwitterionic pyrazolo[3’,4’:4,5Ipyrimido[6,l-a1isoquinolines lla,b and 16a,b,pyrazolo[3’,4‘:4,5lpyrimido[6,l~lphthalazine 6b, and pyra2010[3’,4’: 4,5]pyrido[6,1-alpyrimidines 16a,b are obtained. Additionally, the novel cycloaddition products with triazolinediones, the pyrazolo[3,4-el[1,2,41triazolo[l,2-a][1,2,41triazinediones 9a,b, are described. The isolation of the dihydro compound 4 and the phthalazinium salt 6 supports a stepwise mechanism for the zwitterion formation. While the influence of the aromaticity of the iminophosphorane component appears to be negligible, the aromaticity of the hetarene component determines the limitations of this versatile reaction. X-ray structures of l l a , 6b, and 16b as well as U V - , MS-, and NMR-spectra and semiempirical calculations confirm the zwitterionic character of the reaction products. Introduction Recently, we reported on a novel three-component heteroannulation reaction which converts the iminophosphorane of 6-aminouracil into heterooligocyclic ring s y s t e m ~ on ~ ~ treatment ’~ with an excess of an aryl isocyanate in the presence of a hetarene. Most probably, this reaction proceeds via the initial formation of a carbodiimide from the iminophosphorane and the isocyanate (by an aza-Wittig process) which reacts subsequently with the hetarene to give a [4 21-cycloadduct. The latter one undergoes a final oxidation affording heterocyclic zwitterions. The conditions and limitations of this reaction are well documented for the heterocyclic substrate 6-aminouracil, but no heteroaromatic iminophosphorane species has been examined up to now. While for the uracil substructure in the reaction products a stabilizing effect due to the #?-enaminocarbonyl chromophore is to be expected (and in fact has been observed3b),such considerations cannot be taken into account for aromatic iminophosphoranes. Hence, a different behavior was expected. Furthermore, it was of interest whether the final oxidation step is influenced by the nature of the iminophosphorane component. It appeared t o be advantageous to compare a heteroaromatic iminophosphoranewith a nonaromatic analog possessing a #?-enaminocarbonyl substructure. In order to minimize steric effects, we chose the pyrazole

+

t Institut ftir Organische Chemie und Biochemie.

* Institut ftir Anorganische Chemie der Universitlit.

* Abstract published in Advance ACS Abstracts, June 1,1994.

(1) Part 4 of our series: Three-component cyclizations with heterocyclic iminophosphoranes;Part 3 see ref 3b. (2) Taken in part from the Ph.D. thesis of C. Bamberg, Universitiit Bonn, 1992-1994. (3) (a)Wamhoff, H.;Schmidt, A.; Nieger, M. Tetrahedron Lett. 1991, 4373. (b) Wamhoff, H.; Schmidt, A. J. Org. Chem. 1993,68, 6976. (c) Wamhoff, H.;Schmidt, A. Heterocycles 1993,36, 1055. (d) Kosower, E.M. J.Am. Chem. Soc. 1W8,80,3253. (e) Kosower, E.M.; Ramsey, B. G. J . Am. Chem. Soc. 1@69,81,856.(0Reichardt, C.Angew. Chem. 1@7@,91,119. (g) Reichardt, C.;Mfiller, R. Liebigs Ann. Chem. 1976, 11,125 and literature cited therein. (h)Liptay, W. Angew. Chem. 1989, Schupp, W.; Kirfel, A.; Will,G. J.Org. Chem. 61,195. (i) Wamhoff, H.; 1@86,61,149. (i)Wamhoff, H.;Schupp, W. J . Org. Chem. 1@86,61, 2787.

derivatives 1 and 13 for our investigations, which were prepared from the corresponding amines by standard meth~ds.~’J Their reaction with a broad range of Merent hetarenes and isocyanates promised to enable a versatile access to novel and hitherto unknown tri- and tetracyclic ring systems with interesting steric and electronic properties. Besides, polyheterocyclic compounds are known to possess various biological activities and the resulting fused pyrazoles are of interest as potential bioactive lead substances4 or dyes.

Results and Discussion Reactions of the Pyrazole Derivative 1. The pyrazole iminophosphorane 1 reacts with various isocyanates and hetarenes in a three-component reaction as described for 6-aminoura~i1,3a-~ affording the heteroannulated pyrazoles 6b and lla,b as the final products (Scheme 1 and 2).6a Usually, acetonitrile is used as a solvent; a 3-fold excess of the hetarene component is added together with 3-10 equiv of the isocyanate to the suspension of the iminophosphorane. After addition of the components, the resulting mixture is heated to gentle reflux for ca 3 h. The progress of the reaction can be easily monitored: At the beginning the clear solution turns light yellow upon warming. Above 60 “C the color of the solution becomes increasingly intensive (red, orange, or yellow), indicating the formation of the zwitterions. The most interesting and detailed investigations were conducted with phthalazine 3 as the hetarene component (Scheme 1). Here, as long as an 2-fold excess of the isocyanate is employed, two products are obtained in the reaction: On cooling of the reaction mixture to room temperature a solid precipitates which was identified as the dihydrotetracycle 4. The removal of the solvent (4) (a) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry;Pergamon Press: Oxford, 19&i;Vol. 5, p 343, and references cited therein. (5) (a) Only few representative compounds obtained are described in this paper. “he reaction appears to be of quite general applicability. (b) w h e r details regarding this unexpected reaction are currently under investigation and will be published elsewhere.

0022-3263/94/1959-3985$04.50/00 1994 American Chemical Society

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10

-nI

.. . .

E t - 4 0

7

Et

6B

affords an oily residue, which is triturated with warm ethanol. From the solution thus obtained, additional 4 crystallizes together with diarylurea which is the main byproduct. On further concentration, the monohydrohetarenium ureate 5 is obtained from the ethanolic filtrate. If less than 2 equiv of the isocyanate are present in the reaction mixture, the dihydro compound 4 becomes the main product together with traces of the pyrazolylsubstituted derivative 7 resulting from a formal substitution of the aniline moiety by a second pyrazole amine." The dihydrotetracycle 4 can be oxidized with KMn04 to give the zwitterion 6. This is well generated from the monohydro salt 6 on treatment with a base such as NaOH or NaH. Unexpectedly, no reaction is observed employing pyridine and substituted pyridines like y-picoline. Similarly, isoquinoline 10 as the hetarene component gives good results: after chromatographic purification the zwitterions lla,b are obtained in pure isoquinoline or in acetonitrile in ca. 40% yield. In this case no detectable amounts of any di- or monohydro intermediates are formed which were isolated from acetonitrile for the uracil derivative 12 (Scheme 2).3bThe zwitterions are easily identified by their color and their impressive negative solvatochromism (vide infra). Additionally, the lH-NMR signals of the hetarene part of 6 and 11 show a significant downfield shift of about 1.6-2 ppm. The structures of the monohydro compound Sb and the zwitterion l l a are confirmed by X-ray diffraction analysis. The three differently hydrogenated derivatives 4-6 demonstrate the alterations in their electronic systems with their 'H-NMR shifts. For the dihydro compound 4b the signal of the angular proton H-12b is found at 5.75 ppm and the H-1 signal at 8.2 ppm. While the H-12 signal cannot be unambiguously identified (between 7.45 and 7.65 ppm), the H-8 signal appears at 7.70 ppm (the signal assignments are based on H,H-COSY experi-

Et

Et

6A

5

Scheme 2 R-NCO 2

Me

fi

12

ments). In the monohydro salt 5b the phthalazine moiety has rearomatized and is positively charged. Consequently, all phthalazine signals show a significant downfield shift of about 1-1.3 ppm. The H-8 signal with 9.9 ppm and the H-12 signal with 8.65 ppm indicate the positive charge. The downfield shift of H-1 (found at 9.5 ppm) suggests that this proton is in the vicinity of the positively charged aromatic ring. As can be expected, no H-12b signal is found. The NH signal shifts to 11.4 ppm (from 9.15 ppm) and is significantly broadened due to the inability of the phthalazine N-7 atom to enable a hydrogen bond, while in 4b the NH signal is very sharp corresponding to a limited exchangeability of the proton. In the zwitterion 6b,the negative charge of the pyrazole part decreases the shifts due to its anisotropic effect. H-1

Synthesis of Zwitterionic Heteropolycyclic Pyrazoles Scheme 3

I

Me

13

a: R = H

.) 10

15a,b

16a.b

a: R = ~ - c I - PR~=, H b. R = 4-CI-3-EtO-Ph, R' = Me

appears at 8.8 ppm (a decrease of 0.7 ppm), H-8 a t 9.3 ppm, and H-12 at 8.25 ppm. The altered substituent effect of the tetracycle is reflected in the two signal groups of the 4-chlorophenyl moiety; its AA'BB signal pattern is shifted upfield for about 0.4 ppm in comparison with the monohydro salt. Reactions of the Nonaromatic Pyrazole 13. Despite its nonaromaticity,6the pyrazolone iminophosphorane 13 shows a behavior analogous to 1 and is converted into the zwitterions 16 and 16 by the same procedure (Scheme 3). In contrast to the pyrazole 1, the pyrazolone 13 undergoes a three-component reaction7aas well with pyridine and pyridine derivatives. Thus, treatment of the carbodiimide generated in situ from 13 and aryl isocyanate 2 with pyridine 14a or y-picoline 14b leads to the formation of the zwitterions lSa,b. In accordance with the suggested mechanism is the observation that ethyl nicotinate as the hetarene gives only low yields of the zwitterion independent from the presence or absence of a solvent. For the pyrazolones, too, isoquinoline 10 appears to be the first-rate hetarene as it gave the best results in the cyclization reaction. The resulting zwit(6)(a) The NMR spectra ('H and 13C) of 13 in polar DMSO clearly show the presence of a nonaromatic proton (3.4ppm) attached to a sp2-carbon. (b) Katritzky, A. R.; Karelson, M.; Harris,P. A. Heterocycles 1991,32,329. (e) Wiley, R. H, Wiley, . Pyrazolones, Pyrazolidinones and Derivatives. In Weissberger, A. The Chemistry of Heterocyclic Compounds; Interscience Publishers: New York, 1964;Vol. 20,p 12. (7)(a) Under the usual conditions, the reaction of a 1:3:3mixture of 15,q-chlorophenyl isocyanate andphthalazine afforded a compound ;hich is most probably the monohydro derivative. Unfortunately, it - As impossible to characterize the compound completely up to now. b) An X-ray structure analysis of 9a has been carried out. An ORTEP diagram is shown in Figure 6.

J. Org. Chem., Vol. 59, No. 14, 1994 3987 terions 16a,bshow a typical negative solvatochromism3d-h comparable to that of the uracil derivative^.^^ Obviously, the aromaticity of the iminophosphorane component is of low significance for the feasibility of this reaction. Both the pyrazole derivative and its nonaromatic pyrazolone analog can be converted into zwitterions with comparable yields. On the other hand, the aromaticity of the hetarene component seems to influence the course of the reaction. Mechanism. Our experimental results lead to the following mechanism (see Scheme 1)which agrees well with that proposed by Wamhoff and Schmidt3b In the first step, the iminophosphorane (e.g. 1) undergoes an aza-Wittig reaction with the isocyanate component 2 yielding a carbodiimide 1A Next, the hetarene component (here 3) attacks a t the electrophilic carbodiimide carbon atom to give the intermediate 1B in a reversible step. The resulting ylide 1B is converted into the dihydro intermediate 4 via an intramolecular substitution reaction. Oxidation of 4 gives the final product 6. Although it is possible to represent our novel heterocyclic systems by several Lewis structures, only one uncharged crossconjugated form can be written, which is obviously disfavored in formula 6A for instance, both the pyrazole and the pyridazine part have lost their aromaticity. For the pyrazole derivatives,the aforementionedmechanism was supported by various observations. Firstly, the carbodiimides could be intercepted by the strong dienophile 4-aryl-triazolinedione (4-Ar-TAD, 8) yielding the novel tricyclic pyrazolo[3,4-el[1,2,4ltriazolo[l,2al[l,2,4ltriazines 9a,b (Scheme 1)as a result of a cycloaddition reaction of the 2-azadiene moiety present in the carbodiimides.% Secondly, as no 13C-"Ft experimentswere obtainable with the carbodiimides due to their transient nature, we carried out some semiempirical calculations on them. We chose the AM1 method by Dewar et aL8 for this purpose because it was shown that this method is sufficiently suited to reproduce the geometries of most heterocyclic systemss and because we did not intend to calculate transition states. The calculated electrostatic potentiallo is strongly positive around the carbodiimide carbon center. Thus, a nucleophilic attack by a heteroatom of an arene seems to be favored. Furthermore, the orbital coefficients indicate the absence of any isolated diene system capable of a pericyclic reaction. The resulting ylide 1B is stabilized by conjugation. The subsequent cyclization step was of special interest. While it is possible to consider the ring closure as a 1,Sdipolar cyclizati~n,~~ this is not likely for delocalized systems as the pyrazoles (with a calculated Bird-aromaticity index" ofZs = 69.8, vide infra). Thus, we regard this cyclization as an intramolecular substitution reaction, yielding a dihydro product comparable to 4A. As was observed by van der Plas et al.12 for extremely electron-deficient heteroaromates, nucleophilic substitution reactions on (8)(a) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F. J. Am. Chem. M.J. S.;Holder, A. J. Heterocycles 1989,28,1136. (9)(a) Katritzky, A. R.; Szafran, M.; Malhotra, N.; Chaudry, S. U.; Anders, E. Tetrahedron Comput. Meth. 1990,5, 247. (b) Katritzky, A. R.; Barczyneki, P.; Musumarra, G.; Pisano, D.; Szafran, M. J.Am. Chem. Soc. 1989,111,7. (10)Hyperchem release 3.0 (Autodesk Inc.) on a PC with 16 MB RAM, convergence gradient 0.1. (ll)(a)Bird, C. W. Tetrahedron 1986, 41, 1409. (b) Bird, C. W. Tetrahedron 1986,42,89. (12)(a) Van der Plas,H.C.; Chupakhin, 0. N.; Charushin, V. N. Tetrahedron 1988,44,1.(b) Van der Plas, H.C. J.Heterocyclic Chem. 1988,25,831. Soc. 1985,107,3902. (b) Dewar,

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n

c1

h

4

C12h

CH

@ l l J

Figure 2. ORTEP diagram of the X-ray structure of 5b. 50% thermal ellipsoids, one of the two independent molecules.

Figure 1. Electrostatic potential 160 pm above the plane marked by the three circles. Continuous lines: positive potential; dashed lines: negative potential; -0.2 t o 0.2 au. such hetarenes can lead to the formation of sometimes isolable a-adducts which have to be oxidized with KMn04 to yield the desired products. The hetarenium moiety present in the ylide 1B can certainly be considered as being extremely electron-deficient. On the other hand, the 4-position of pyrazoles is known t o be nu~leophi1ic.l~ This nucleophilicity is enhanced by the conjugation with the negative part of the ylide in 1B. The calculated electrostatic potential (AM1) for such an ylide is presented in Figure 1. The potential diagram reveals that a substitution reaction is well possible. The tautomerism, forming a 1,Cdihydro product 4B,reconstitutes aromaticity in the pyrazole ring. Interestingly, both the pyrazole as well as the pyrazolone derivative undergo oxidation under appropriate conditions so that the zwitterions 11,15, and 16 can be isolated. This “oxidation” step represents further evidence for an intramolecular substitution reaction. Van der Plas et a1.12 have pointed out that the substitution of an aromatic H-atom is facilitated if the electron deficiency is enhanced. In this case, a hydride ion is formally superseded. Thus, the “oxidation”has to be considered as a two-step process involving formal hydride and proton displacements. “hat this is indeed the case in the formation of the pyrazole zwitterions was impressively demonstrated by the isolation and X-ray structure determination of the tetracyclic arenium ion 5b.14 Here, the hydride is already displaced, while the proton at the amine position is still present. Besides, the X-ray single-crystal structure of 5b (Figure 2) unambiguously proves the tautomeric shift of one H-atom (13)(a) Burton, R. E.; Finar, I. L. J. Chem. SOC.(B) 1970,1692. (b) Simay, A.;Takfics, K.; Horvfith, K.; Dvortsdk, P. Acta Chim. Acad. Sci. Hung. 1980,105,127. (c) Dorn,H. Chem. Heterocycl. Compd. (Engl. Transl.) 1980,16,1. (14)The origin of the chloride anion detected in the X-ray structure of 6b is not sufficiently explained. The only possible chloride sources were the chlorophenyl substituents and the solvent component CDCIs.

of the primary substitution product 4A to this amine position. The “hydride”is probably accepted by one molecule of the isocyanate (present in excess) which reacts with a second isocyanate molecule to form the counterion of the monohydro salt 5. This is indicated by lH NMR signals similar to those of the corresponding diarylurea with an NH signal referring to only one proton. Besides, the unavoidable generation of the diarylurea even in solvents as toluene is thus explained. A mass spectroscopic examination of 5b revealed the presence of this diarylurea. From the same sample, a zwitterion mass spectrum was obtained after prolonged measurement at 180 “C. As is seen in the lH NMR spectra, the urea and compound 5b are both present in a chromatographically pure sample. While the formation of the primary addition product, as an equilibrium, depends on the basicity of the hetarene component, the subsequent intramolecular substitution is dependent on the electron deficiency,which is opposite to the basicity. Hence, the inertness of pyridine and y-picoline (and DMAP) toward the pyrazole derivative in this three-componentreaction is easily explained. While the primary addition products are readily formed, yielding an open-chain ylide, intramolecular substitution does not occur. Van der Plas et a1.12 concluded, that the addition step of the intramolecular substitution occurs more readily with hetarenes of low aromaticity while the hydride abstraction is facilitated by a higher aromaticity of the reconstituted arene. Thus, it can be expected, that pyridines do form the primary adduct but do not undergo the addition of the pyrazole C-4 atom, whose nucleophilicity is limited due to its aromatic conjugation. On the other hand, the pyrazolone iminophosphorane 13, as well as the (uracil-6-ylimino)phosphorane, do react with pyridine due to the greater nucleophilicity of their C-4 and C-5 positions, respectively. This is also in accordance with the observation of Wamhoff and Schmidt in their cross-experiments with differently substituted Besides other methods,16the influence of the aromaticity of the participating species can be estimated by (15)Simkin, B. Y.; Minkin, V. I.; Glukhovtsev, M. N. Mu.Heterocycl. Chem. 1993,56,304.

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Synthesis of Zwitterionic Heteropolycyclic Pyrazoles Bird's aromaticity index I,. It represents the variation of the bond orders in a given cyclic system (which meets the qualitative criteria of aromaticity) and is normalized to be I = 100 for a completely delocalized system (benzene). For a totally localized structure, I = 0 is obtained. As was shown by Katritzky et al.,gbthis index can successfully be applied to all heteroaromates, in which the number of heteroatoms does not exceed that of the carbon atoms. However, highly symmetrical structures cannot correctly be estimated.14 In our case, the application of Bird's index shows, that in the zwitterion 11 the isoquinolinium ring has an index of 16,6 = 57.3, and in 5 for the phthalazinium ring 16.6 = 65.2. (The index 16,sreferring to a bicyclic 6,6-ring arene was chosen because the X-ray structures imply two separated aromatic systems in the zwitterions, vide infra). For the 10-membered,bicyclic heteroarenes, the calculated (AM1) bond lengths lead to slightly higher aromaticity indices. Still, the value for pyridinium with 1 6 = 74.4 is the highest,I6proving that here the t e m p o r q suspension of aromaticity is most unfavorable. On the other hand, the reaction with isoquinoline preserves the aromaticity in the benzo part of the bicyclic isoquinoline structure and its aromaticity rises to a value ofI6 = 83.4. It can thus be concluded that despite the steric demands in tetracyclic systems such as 6 or 11, the reaction of bicyclic arene components, e.g. phthalazine or isoquinoline, is favored due to the fact that the aromaticity of the species is never totally suspended. Once the a-complex is formed the H-shift after the formation allows rearomatization. Hence, it can be expected,that the equilibrium of these two steps, addition and tautomerism, is shifted to the right side of the equation due to the aromatic stabilization of the iminophosphorane component. The hydride elimination following, now regains the aromaticity of the hetarene component (in the case of the bicylic hetarenes for the N-containing ring system). Structural Features. The three-component reaction of the pyrazole derivatives 1 and 13 with heteroaromatic bicyclic compounds such as isoquinoline leads to the formation of tetracyclic ring systems in which the substituents a t the 1-and 12-positionsare in relatively close positions. Consequently, we investigated the possibility of helical zwitterions. The calculated structures indicated the generation of helical products with torsion angles of about 17" between the positions 12 and 12c. To verify this hypothesis we carried out the measurement of a NOE-difference spectrum on compound l l a . Although only qualitatively, a nuclear Overhauser amplification of about 23% made a greater distance between the two protons at the positions 1and 12 unlikely. The X-ray single crystal structure (Figure 3) of the zwitterion 16b confirmed this conclusion: the observed torsion angle between C-12 and C-12c amounts to only 4.2" which means an almost total planarity of the tetracyclic system. To achieve this planarity, the zwitterionic system 16b is distorted at the C12a-Cl2b bond, the length being 144.4(5) pm and shortened at the C7-C8 bond to only 132.7(5) pm. These bond lengths are at the outer margins for the values possible in aromatic systems.gb Interestingly, the aryl substituent seems to be separated from the zwitterion's negative partial charge (despite their conjugation). While the C5-N20 bond possesses the bond order of a double bond (with a length of 129.3(4) (16)Pyridinium N-oxide. Taken from ref 8b.

CH

Figure 3. ORTEP diagram of the X-ray structure of 16b.50% thermal ellipsoids.

C14

ClO NZ

C1

Figure 4. X-ray structure of lla. A view from the side demonstrates the planarity of the tetracyclic system.

pm), the N20-C21 bond has an increased a-character (length: 140.1(4)pm). Furthermore, the W-NMR shifts of the N-aryl substituent show almost no differences compared to uncharged anilines. Additionally, the single crystal X-ray analysis documents the charge separation between the isoquinolinium unit and the negative part in the zwitterion: the increased length of the C5-N6 bond (147.5(4)pm (corresponding to a single bond)) leads to the conclusion that there is no n-interaction between the isoquinolinium unit and C5. On the other hand the system is stabilized by the C12b-Cl2c bond with 141.7(5) pm which has some n-contributions. The corresponding bond lengths obtained for the analogous pyrazole zwitterion from the single crystal X-ray analysis of l l a (Figure 4) are as follows: C5-N6 147.9(2) pm, C12bC12c 139.9(2)pm, C12a-Cl2b 145.1(2)pm, and C7-CS 133.2(3) pm. A further information is provided by the evaluation of the bond lengths: no particular bond length alternance pointing to a localized cross-conjugatedstructure is observed, supporting the conclusion that two seperate aromatic subsystems form the zwitterionic compounds. Although the AM1-optimized structure of l l a differs slightly from the one determined experimentally, the charge separation is well documented by the calculated electrostatic potential (Figure 5). The tetracyclic ring

3990 J. Org. Chem., Vol. 59, No. 14, 1994

Wamhoff et al.

Figure 6. ORTEP diagram of the X-ray structure of Sa. 50% thermal ellipsoids.

Figure 5. Electrostatic potential 300 pm above the plane of the tetracyclic system. Continuous lines: positive potential; dashed lines: negative potential; -0.02 to 0.02 au. system appears to be quite rigid. This rigidity is reflected in the 1R-spectra of t h e zwitterions which contain a relatively small number of bands. Additionally, in the MS only a small number of peaks are observed at masses below the molecular mass due to the stability of the polycyclic ring system. All zwitterions exhibit a pronounced negative solvatochromic effect. For t h e pyrazolone 16a, for instance, A,, of the VIS-absorption is shiRed from 407 nm in polar 2,2,2-trifluoroethanol to 441 n m in CC4. The enhanced delocalization ofthe negative charge in the zwitterion l l a prepared from the aromatic pyrazole iminophosphorane is impressively demonstrated by its M,, of 120 n m between trifluoroethanol a n d CCld. This shift exceeds by far the effect found for the uracil analogs.3b

X-ray Crystallographic Studies of Sb, 9a, l l a , and 16b.l' All X-ray data were collected at room temperature. The structures were solved by direct methods (SHELXTL-Plus). All non-hydrogen atoms were refined anisotropically, H atoms were refined by using a riding model, and H(N) were refined free (SHELXTL-Plus for 9a; SHELXL-93 for 6b, lla, and 16b). An extinction correction was applied on Oa, l l a , a n d 16b, a n d a n absorption correction on t h e basis of IJJ scans on l l a a n d 16b, respectively. Programs: G.M. Sheldrick, SHEIXTLPlus, Siemens Analytical X-ray Instruments Inc. , Madison, Wisconsin, 1989. G.M. Sheldrick, SHELXL-93, Univ. of Gottingen, FRG, 1993.

Experimental Section Methods and Materials. Analyses were carried out by the Mikroanalytisches Laboratorium des Instituts fur Organische Chemie und Biochemie, Universittit Bonn. NMR spectra were recorded on either Bruker WH-90, WH-200, or WM-250 instruments. The mass spectrometers (MS) used were the A.E.I. (Kratos)MS-30 and MS-50. Despite prolonged combustion times, some compounds failed to give satisfactory elemental analyses due to their extraordinary stability. In(17) The author has deposited atomic coordinates for this structure with the Cambridge Crystallographic Data Centre. "he coordinates can be obtained, on request, from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 lEZ, UK.

frared spectra were obtained on a Perkin-Elmer 157-G spectrophotometer, and UV spectra were recorded on a Beckman DU-640 spectrophotometer. Melting points are uncorrected. All solvents and liquid reagents (MeCN and hetarenes) were distilled prior to use and dried as usual. All other commercially available chemicals were used without further purification. The synthesis of the 5-amino-1,2-dihydro-lmethyl-2-phenylpyrazol-3-one was accomplished as previously reported,'*J9 while the 5-amino-l-ethylpyrazolewas purchased from the Aldrich Chemical Co. Light petroleum ether (bp 4060 "C) was used whenever this solvent was required. The reactions were carried out in predried glassware under an argon atmosphere. For chromatographic separations, Merck silica gel 60 (70-230 mesh) was used. Preparation of the Iminophosphoranes 1 and 13. To a suspension of the aminopyrazole in 75 mL of dry toluene were added P P h , C2Cl8, and NEt3 in the molar ratios given below and heated t o reflux for 3 h. The hot pale-yellow solution was separated from the precipitated NEtpHC1 and the solvent was distilled off in uucuo to afford a crude solid which was recrystallized from ethanol. S-[(Triphenylphosphoranylidene)aminol-l-ethylpyrazole (1). A n amount of 5 g (40 mmol) of the aminopyrazole, 14.15 g (54 mmol) of PPh3, and 8.5 g (40 mmol) of CZC~S were heated together with 12 mL (80 mmol) of NEt3 to yield 9.8 g (66%)of 1: mp 111-112 "C; IR (KBr) 3040,2975,2925,1430 cm-l; W-vis (1,4-dioxane) I (log E) 242 (3.46) nm; 'H NMR (90 MHz) (CDC13) 6 1.4 (t, 3, J = 7.2 Hz), 3.1 (9, 2, J = 7.2 Hz),7.25 (d, 1, J = 2.1 Hz), 7.3-7.7 (m, 16);13CNMR (50 MHz) (CDCl3) 6 14.84, 45.64, 90.79 (d, Vpc = 8.7 Hz, C-41, 128.48 = 108.3 Hz,C-lo), (d, 3Jpc = 12.8 Hz, C-12), 129.43 (d, 'JPC 131.93 (d, 2Jpc = 9.6 Hz, C-11), 132.16 (d, 4 J=~3.2 Hz, C-13), 133.42(d, 4Jpc= 2.5 Hz, C-3), 137.38 (d, 'Jpc = 21.2 Hz, (2-5); EIMS (70 eV), mlz (re1 inten) 371 (M+, 100). Anal. Calcd for C23HzzN3P: C, 74.38; H, 5.97; N, 11.31. Found: C, 74.25; H, 6.00; N, 11.05.

5-[(Triphenylphosphoranylidene)aminol-l,2-dihydrol-methyl-2-phenylpyrazol-3-one (13). An amount of 10 g (36 mmol) of the aminopyrazolone,14.15g (54 mmol) of PPh3, 8.4 g (36 mmol) of C2ClS,and 10 mL (72 mmol) of NEts were used: yield 13.4 g (83%);mp 209 "C; IR (KBr) 3045,1650,1590, 1575, 1430 cm-'; W-vis (1,Cdioxane)I (log E) 264 (2.84) nm; 'H NMR (250 MHz) (CDC13) 6 4.25 (s, 3), 7.1 (t, l),7.3 (t, 21, 7.4-7.6 (m, 13), 7.6-7.75 (m, 5); 13CN M R (60.25MHz) (CDCld 6 36.14,81.08, 122.49, 124.27, 127.11, 128.61, 128.74, 128.93, 129.13,132.35,132.52,132.68, 132.75,132.79,138.20,166.91, 167.10, 169.43; EIMS (70 eV), mlz (re1 inten) 449 (M+, 100); HRMS calcd for C2sH2&OP mlz 449.1657, found 449.1657. Anal. Calcd for C 2 & , a 3 0 P : C, 74.82; H, 5.38; N, 9.35. Found: C, 74.51; H, 5.41; N, 9.32.

General Procedure for the Preparation of the Pyra-

zolo[3',4':4,5]pyrimido[6,1-a] isoquinolinium Betaines, (18) De Graef, H.; Ledrut, J., Combes, G. Bull. SOC.Chim. Belg. 1952, 61,331.

(19) Ito, I. J.Pharm. SOC.Jpn. 1956, 76,820.

J. Org. Chem., Vol. 59, No.14, 1994 3991

Synthesis of Zwitterionic Heteropolycyclic F'yrazoles

Table 1. Crystallographic Data and Summary of Data Collection and RefinementQ sb Sa 1la formula cryst syst space group a,A b, A c, A

a,deg

B 1

deg

Y , deg

v,A3 2

e

calc, g P , l-"

F(OO0)

diffractometer " max 26, deg no. of unique data full-matrix least-squares refinement on no. of variabledrestraints R [for Z > 2401 wR2

g1k32

CssHzsC4&0 tri_cclinic P1 (N0.2) 13.265(3) 15.438(3) 17.626(4) 88.91(1) 68.80(1) 72.56(1) 3195(1) 4 1.44 0.41 1424 Nicolet R3m Mo Ka 0.71073 50 11237

F

84716 0.046 0.122 0.0628/0

CzzHziNiG tljclinic P1 (No.2) 6.244(1) 13.109(1) 13.605(1) 101.46(1) 93.77(1) 91.35(1) 1088.3(1) 2 1.32 0.76 452 Enraf-Nonius CAD4 Cu Ka 1.54178 140 4130 F 293l1 0.066b

16b

C2iHi7Ns monoclinic P 2 l l ~(NO.14) 10.012(1) 12.676(1) 13.919(1)

monoclinic m1/C (N0.14) 15.204(4) 15.008(1) 10.463(2)

106.15(1)

101.05(2)

1696.8(2) 4 1.33 0.65 712 Enraf-Nonius CAD4 Cu Ka 1.54178 120 2506

2343.2(8) 4 1.41 1.75 1032 Enraf-Nonius CAD4 Cu Ka 1.54178 120 3466

23912 0.040 0.120 0.0598l0.3622

328/0 0.052 0.158 0.090110.0831

F

+

+

c2&22cl&02

F

+

R = ZM'ol - IFdlElFol;wR2 = [C[w(Fo2- Fc2)zYZ[w(Fo2)211m with w = 14a2(Fo2) ( ~ I P )g@l ~ and P = (Fo2 2Fc2)/3. For 3284 reflections F > 3 0 0 , R, = 0.073; R, = UIFol - IFCl)wmEIFolwm and w = l/[u2(Fo)+ 0.0O05Fo21. solid (4b)precipitated which was a t e r e d off. More of compound 4b together with N,"-bis(4-chlorophenyl)urea were obtained from the concentrated ethanolic solution. Column chromatography of the collected solids on silica eluting with petroleum ethedethyl acetate, 15,afforded yellow platelets: yield 145 mg (13%);mp 187 "C dec; IR (KBr) 3360,3020,2970, 1590, 1570, 1545, 1520 cm-l; UV-vis (CH2C12) 1 (log a) 287 (3.24) nm; lH N M R (250 MHz) (DMSO) 6 1.35 (t, 3, J = 7.26 solid. Molar ratios, further purification, and the reaction times Hz),4.05 (q,2, J = 7.25 Hz), 5.75 (8, 1),7.35(d, 2, J = 8.6 Hz), (in parentheses) are described below. 6(Wenylamino)-l~~iaydro-S-ethylpyrazol0[3',44~]- 7.45-7.65 (m, 4), 7.7 (8, l), 7.85 (d, 2, J = 8.6 Hz), 8.2 ( 8 , 11, 9.15 (8, 1); 1% N M R (60.25 M H z ) (DMSO)6 15.08,41.11,54.05, pyrimido[6,l-~lphthalazine(4a). Phenylisocyanate (360 95.61, 122.41, 123.40, 124.35, 125.08, 126.14, 128.12, 128.46, mg, 3 mmol) and phthalazine (400 mg, 3 mmol) were added 131.55, 132.19, 134.16, 138.13, 142.24, 143.69, 146.79; EIMS to the imino-phosphorme 1 and heated to reflux temperature (70 eV) mlz (re1 inten) 376 (M+, 57); HRMS calcd for c2&7' (3h). On cooling to room temperatuke a light yellow solid (4a) ClNe mlz 376.1203, found 376.1153. Anal. Calcd for C20H17was obtained. More of 4a together with N,N'-diphenylurea CIN6: C, 63.74; H, 4.55; N, 22.30. Found: C, 64.18; H, 4.60; precipitated from the concentrated ethanolic solution. ChroN, 21.88. matography of the collected solids on silica eluting with 6-[(4-Chlorophenyl)aminol-S-ethylpyrazolo[3',4':4,61petroleum etherlethyl acetate 1:5 afforded light yellow platelets, yield 115 mg (11%); mp 192-195 "C; IR (KBr)3340,3025, pyrimido[6,lalphthala" * 'um Ion (6b). The residue of the 2975,1595,1575,1550,1520 cm-l; lH N M R (250 M H z ) (CDCW concentrated ethanolic solution obtained above was chromatographed on silica eluting with petroleum ethedethyl acetate, 6 1.45 (t, 3), 4.2 (9, 21, 5.7 ( 8 , l),7.2-7.6 (m, 9), 7.85 ( 8 , l), 2:15, to give a deep yellow solid which remained on the 8.35 (s,l); 13CN M R (60.25 MHz) (DMSO)6 15.06,41.91,54.47, 95.77, 121.08, 123.53, 124.62, 127.64, 128.35, 128.68, 131.40, adsorbent bed and could be isolated by Soxhlet extraction with 132.21, 134.26, 137.35, 143.18, 146.32; EIMS (70 eV) mlz (re1 ethanol; yield 233 mg (48%);mp 213-214 "C; IR (KBr)3320, inten) 342 (M+, 52); HRMS calcd for C2oHl& mlz 342.1593, 3050, 2970, 2930 cm-'; UV-vis (CHzC12) 1 (qualitative) 480, found 342.1584. 310, 265 nm; lH N M R (90 MHz) (DMSO) 6 1.45 (t, 3, J = 7 Hz), 4.4 (9, 2, J = 7 Hz), 7.4 (8, l), 7.55 (d, 2, J = 7.5 Hz), 7.9 5-(Phenylamino)-3-ethylpyrazolo[3',4':4,6lpyrimido(d,2,J=7.3Hz),8.4(t,l,J=8.1Hz),8.45(t,l,J=8.1Hz), [6,l-~]phthalazMum Ion (Sa). The residue of the concen8 . 6 ( d , l , J = 8 . 0 H z ) , 9 . 3 5 ( d , l ,J = 7 . 9 H z ) , 9 . 5 ( ~ , 1 ) , 9 . 8 8 ( ~ , trated ethanolic solution obtained above was chromatographed 1); 13CNMR (50MHz) (DMSO)6 14.11,42.01,102.19, 119.14, on silica eluting with petroleum ethedethyl acetate, 2:15, 124.36,124.55,128.53,128.62,129.57,135.77,136.17,136.86, affording an intense yellow amorphous solid which remained 137.26, 138.56, 143.18, 148.13, 149.25, 152.31; EIMS (70 eV) on the adsorbent bed and could be isolated by Soxhlet mlz (re1inten) 374 (M+, 100); HRMS calcd for C~OHI&~& mlz extraction with ethanol: yield 209 mg (47%);mp 204-205 "C; 374.1046, found 374.1044. IR (KBr) 3350, 3050, 2980, 2930 cm-l; lH NMR (90 MHz) (DMSO) 6 1.4 (t, 3, J = 7.1 Hz), 4.35 (q,2, J = 7.0 Hz), 7.6 (8, S-[(4-Chlorophenyl)aminol-3-ethylpyrazolo~3',4':4,61l), 7.2-7.7 (m,31, 7.9 (d, 2, J = 7.9 Hz), 8.4 (m, 2), 8.75 (d, 1, pyrimido[6,la]phthalazinium Betaine (6b). A solution J = 7.5 Hz), 9.4 (d, 1, J = 8.1 Hz), 9.5 (8, 11, 9.9 ( 8 , 1); 13C of 24 mg (0.15 "01) KMn04 in 10 mL of H2O was added NMR (50 MHz) (DMSO)6 14.23,45.15, 102.17, 123.6, 124.66, dropwise to a solution of 60 mg (0.15 mmol) of 6b in 10 mL of 124.79, 125.68, 128.81, 128.9, 129.98, 136.97, 136.97, 137.04, ethanol and stirred for 5 h at room temperature. The 137.39, 143.67, 148.18,148.54, 149.18; EIMS (70 eV), mlz (re1 precipitate ( M n 0 2 ) was filtered off and extracted three times inten) 340 (M+, 94); HRMS calcd for C20HlsNemlz 340.1436, with CH2C12. The mother liquor was extracted twice with found 340.1440. CHC13. The combined organic layers were dried over MgS04 was distilled off in vacuo. Column chroma6[ ( 4 C h l o r o p h e n y l ) ~ o ] - l ~ ~ ~ l and p ~the l solvent ~ tography on silica (petroleum etherlethyl acetate, 2:15) af[3',4':4,5lpyrimido[6,l-a]phthalazine (4b). 4-Chlorophenyl forded a deep red solid: yield 50 mg (89%); mp 205-206 "C; and phthalazine (400 mg, 3 "01) isocyanate (460 mg, 3 "01) IR (KBr) 3040,2975,2945,1630,1565,1540 cm-l; UV-vis (1,4were used (3 h). On cooling to room temperature a light yellow

the ~ ~ - p y r a z o l o [ 3 ' , 4 ' : 4 , S l p y r i m i d o ~ 6 , l a 3 p h and -phthalazinium Ions. A stirred suspension of the iminophosphorane 1 (500mg, 1.3 mmol) and the hetarene in dry acetonitrile was treated with the isocyanate and refluxed for the period given below. The solvent was distilled off in vacuo and the deeply colored oily residue was treated with a small amount of hot ethanol to afford in some cases a crude

3992

J. Org. Chem., Vol.59,No.14,1994

dioxane)d (log E) 502 (2.87),362 (3.18), 304 (3.29) nm; 'H NMR (250 MHz) (DMSO) 6 1.35 (t, 3, J = 7 Hz), 4.05 (9, 2, J = 7 Hz), 7.25 (d, 2, J = 8.3 Hz), 7.3 (d, 2, J = 8.3 Hz), 8.1-8.25 (m, 2), 8.3 (d, 1J = 6.8 Hz), 8.75 ( 6 , l),8.95 (d, 1,J = 7.28 Hz), 9.3 (s, 1); I3C NMR (60.25 MHz) (DMSO) 6 14.03, 40.37, 98.12, 120.82, 123.89, 124.68, 125.06, 125.48, 127.88, 128.22, 134.49,135.39,135.69,143.25,146.77,149.02,149.09,151.90; EIMS (70 eV), mlz (re1 inten) 374 (M+, 100); HRMS calcd for C~oH1.&1N6m/z 374.1046, found 374.1046.

5-(Phenylamino)-3-ethylpyrazolo[3',4':4,5]pyrimido[6,1-~]isoquinolinium Betaine (lla). Phenyl isocyanate

Wamhoff et al. pyrimidinium Betaine (1Sb). The treatment of 13 with 4-chloro-3-ethoxyphenyl isocyanate (650 mg, 3 mmol) in y-picoline afforded a deep orange solid after recrystallization from ethanol: yield 223 mg (44%);mp 206 "C; IR (KBr) 3055,2970, 1670,1600,1585cm-'; UV-vis (1,4-dioxane)1 (qualitative) 418, 346,289 nm; lH NMR (250 MHz) (DMSO) 6 1.35 (t, 3, J = 6.5 Hz), 2.4 (8, 3), 3.1 (s, 3), 4.05 (9, 2, J = 6.5 Hz), 7.0 (d, 1,J = 7.4 Hz), 7.2-7.5 (m, €47.9 (s, l), 9.5 (d, 1,J = 7 Hz); I3C NMR (60.25 MHz) (DMSO) 6 14.25, 15.08, 59.71, 83.18, 109.10, 109.66,114.28,119.85,120.39,122.72,123.34,126.16,126.91, 128.62,129.28,135.95,145.17,146.00, 147.67, 153.38,154.36, 160.57, 160.96; EIMS (70 eV) mlz (re1 inten) 459 (M+, 100); HRMS calcd for C25HzzClNsOz mlz 459.1462, found 459.1456. Anal. Calcd for Cz5HzzClN502: C, 65.29; H, 4.82; N, 15.23. Found: C, 65.20; H, 4.73; N, 15.18.

(360 mg, 3 mmol) and isoquinoline (400 mg, 3 mmoli were added t o the iminophosphorane 1 and heated to reflux temperature (3 h). The crude product was purified twice chromatographically on silica ((i)petroleum etherlethyl acetate, 2:1, (ii) petroleum etherlethyl acetate, 2: 15) and then recrys5-[(4Chlorophenyl)aminolminoll,!2-dihydro-3-methyl-l-oxotallized from acetonitrile to give dark red-violet needles: yield 2-phenylpyrazolo[~,4:4,5]p~mido[6,l-u]isoquinolini178 mg (41%);mp 207-208 "C; IR (KBr) 3040, 2980, 2940, um Betaine (16a). 4-Chlorophenyl isocyanate (460 mg, 3 1630,1570,1540cm-l; UV-vis (1,4-dioxane)I (log E) 507 (2.94), mmol) was added to a suspension of 13 in isoquinoline (5h). 364 (3.39), 307 (3.64), 281 (3.70); IH NMR (90 MHz) (DMSO) The oily residue was subsequently chromatographed on silica 61.38(t,3,J=7Hz),4.15(q,2,J=7Hz),6.9(m,1),7.25(t,eluting with petroleum etherlethyl acetate, 15,affording an 2, J = 7.5 Hz),7.45 (d, 2, J = 7.5 Hz), 7.78 (d, 1,J = 7.75 Hz), orange-coloredamorphous solid yield 235 mg (47%);mp 2277.9 (t, 1,J = 6.89 Hz), 8.06 (m, 2), 8.75 (8,l),9.05 (d, 1,J = 228 "C; IR (KBr)3065,2970,1690,1645,1600,1570cm-l; UV8.3 Hz),9.7 (d, 1,J = 7.76 Hz); 13CNMR (60.25 MHz) (DMSO) vis (1,4-dioxane) 1 (qualitative) 428, 344, 272 nm; lH NMR 6 14.09, 42.28, 99.34, 118.17, 121.78, 123.52, 124.20, 127.02, (250 MHz) (DMSO) 6 3.2 (s, 3), 7.3-7.55 (m, 9); 7.7 (d, 1,J = 127.54,128.12,128.32,128.77,134.27,134.53,135.60,143.73, 7.68 Hz), 7.8 (dd, 1, J = 7.87, 4.12 Hz), 8.0 (d, 2, J = 4.0 Hz), 146.03,146.79, 152.56; EIMS (70 eV), mlz (re1 inten) 339 (M+, 9.5 (d, 1,J = 7.7 Hz), 10.6 (d, 1, J = 8.53 Hz); 13CNMR (60.25 93); HRMS calcd for C21H17N5 mlz 339.1484, found 339.1493. MHz) (DMF) 6 34.88, 89.23, 117.26, 125.13, 125.34, 126.19, Anal. Calcd for C21H17N5: C, 74.32; H, 5.05; N, 20.63. 126.72,127.28,127.31,127.35,128.57,128.75,129.63,132.91, Found: C, 74.08; H, 5.02; N, 20.79. The short distance 135.42,135.93,137.11,148.21,148.31,151.07,161.96,162.09; between 1-H and 12-H has been demonstrated on the basis of EIMS (70 ev) mlz (re1 inten) 451 (M+, 100); HRMS calcd for a (qualitative) NOE experiment: Irradiation on 1-H caused Cz6Hl&lN~Omlz 451.1200, found 451.1200. Anal. Calcd for on NOE amplification of the 12-H signal of about 23%. C&Ii&1N&: c, 69.10; H, 4.01; N, 15.50. Found C, 68.87; 5-[(4-Nitrophenyl)amino] -3-ethylpyrazolo[3',4':4,5lpyH, 4.04; N, 15.60. rimido[6,1-a]isoquinolinium Betaine (llb). 4-Nitrophenyl 5-[ (4-Chloro-3-ethoxyphenyl)aminol-1,2-dihydro-3isocyanate (500 mg, 3 mmol) and isoquinoline (400 mg, 3 methyl-l-oxo-2-phenylpyrazolo[3',4':4,5lpyrimido[6,lalmmol) were heated together with 1 (3 h). The product was isoquinolinium Betaine (16b). 4-Chloro-3-ethoxyphenyl purified on a short silica column eluting with petroleum ether/ isocyanate (600 mg, 3 mmol) was used. The oily residue was ethyl acetate, 2:15. Due t o its insolubility, the betaine chromatographed on silica eluting with petroleum etherlethyl remained on the adsorbent bed and could be isolated by acetate 1:5 to obtain deep orange crystals after recrystallizaSoxhlet extraction with acetone to give brilliant red crystals: tion from ethanol: yield 285 mg (52%);mp 216-218 "C; IR yield 135 mg (27%);mp 293-294 "C; IR (KBr); W - v i s (1,4(KBr) 3060,2975,1670,1615,1590 cm-'; UV-vis (1,4-dioxane) dioxane)1 (qualitative) 557, 418, 366, 257 nm; 'H NMR (250 1(log E ) 430 (2.92), 340 (3.40), 273 (3.65) nm; lH NMR (250 MHz) (DMSO)6 1.45 (t, 3, J = 7.2 Hz), 4.25 (q, 2, J = 7.2 Hz), MHz) (DMSO) 6 1.35 (t, 3, J = 6.9 Hz), 3.2 (s, 3), 4.1 (9, 2, J 7.6 (d, 2, J = 6.9 Hz), 7.8 (m, 11, 7.9 (m, 11, 8.15 (m, 4) 8.9 (d, = 6.9 Hz), 7.0 (dd, 1, J = 8.51, 2 Hz), 7.2-7.6 (m, 9), 7.7 (d, 1, 1,J = 8.2 Hz), 9.1 (d, 1,J = 8.3 Hz), 9.75 (d, 1,J = 8.3 Hz); J = 7.87 Hz), 7.75 (dd, 1,J = 7.8,4.23 Hz), 8.0 (d, 2, J = 3.92 no I3C NMR spectrum available because of insufficient solubilHz), 9.5 (d, 1,J = 7.6 Hz, 10.6 (d, 1, J = 8.6 Hz); no 13CNMR ity; EIMS (70 eV), mlz (re1 inten) 384 (M+,51); HRMS calcd data available because of insufficient solubility; EIMS (70 eV) for C21H16N602 mlz 384.1335, found 384.1337. Anal. Calcd mlz (re1 inten) 495 (M+, 73); HRMS calcd for CzsHzzClN5Oz for C&l6N~Oz: C, 65.62; H, 4.20; N, 21.86. Found C, 65.66; mlz 495.1462, found 495.1455. Anal. Calcd for C2sH22H, 4.16; N, 21.08. ClN5O2: C, 67.81; H, 4.47; N, 14.12. Found C, 67.74; H, 4.51; General Procedure for the Preparation of the BeN, 13.63. taines 15 and 16. The isocyanate component was added to a Preparation of the 8-(4-Ethoxyphenyl)-3-ethyl-S-(phestirred solution of the iminophosphorane 13 (500 mg, 1.1 nylamino)-~,7,7H-pyrazolo[3,4el~l,!2,4l~lo~l~l[1,!2,4lmmol) in 5 mL of the dry hetarene as solvent and heated (max triazine-7,9(8H)-dione (9a). To a stirred solution of the temp 130 "C) over the period given below. The excess hetarene pyrazoleiminophosphorane 1 (500 mg, 1.3 mmol) and phenyl was distilled off in uucuo. Unless otherwise noted, the colored isocyanate (360 mg, 3 mmol) in 10 mL of dry CHzClz under residue was then treated with 20 mL of boiling ethanol t o an argon atmosphere was added dropwise a solution of 444dissolve the triphenylphosphineoxide. Ethanol-soluble prodethoxyphenyl)-TAD(650 mg, 3 mmol) in 10 mL of the solvent ucts crystallized on cooling. Molar ratios, purification, and at a temperature of -15 "C until the color persisted. The reaction times (in parentheses) are described below. solvent was distilled off in uucuo and the brown oily residue 54(4-Chlorophenyl)amino] - 1,2-dihydro-3-methyl1-oxowas treated with hot ethyl acetate to give the crude product 2-phenylpyrazolo[3',44,5lpyrido[6,lalp Bewhich was purified by silica chromatography eluting with taine (15a). 4-Chlorophenylisocyanate (460 mg, 3 "01) was petroleum etherlethyl acetate 2:15 to give colorless needles heated together with 13 in dry pyridine (5 h). The crude solid after recrystallization from ethyl acetate: yield 60 mg (11%); was recrystallized from ethanol: yield 185 mg (42%);mp 236mg (11%);mp 184 "C; IR (KBr) 3250,3100,2980,2930,1760, 238 "C; IR (KBr)3060,2975,1670,1615,1595,1565cm-'; UV1690 cm-'; W-vis (1,Cdioxane) I (log E ) 255 (3.49); 'H NMR vis (l,4-dioxane)I (log e) 428 (2.76), 341 (3.19), 288 (3.55) nm; (250 MHz) (CDCl3) 6 1.45 (t, 3, J = 7.2 Hz), 1.5 (t, 3, J = 7.3 lH NMR (250 MHz) (DMSO)6 3.2 (s,3), 7.3-7.6 (m, lo), 8.2Hz),4.05(q,2,J=7.15Hz),4.15(q,2,J=7.3Hz),7.0(d,2, 8.3 (m, 2), 9.7 (d, 1,J = 7 Hz); no 13C NMR data available J = 6.9 Hz), 7.15 (t, 1, J = 7.3 Hz), 7.4 (m, 41, 7.55 (9, 11, 7.6 because of insufficient solubility; EIMS (70 eV) mlz (re1 inten) (d, 2, J = 7.7 Hz), 9.75 (9, 1); 13C NMR (60.25 MHz) (CDCl3)6 401 (M+,100);HRMS calcd for CzzH&lNs mlz 401.1044, found 15.41, 15.68, 43.61, 64.54, 104.88, 115.97, 121.38, 122.62, 401.1050. Anal. Calcd for C22H16ClN5: C, 65.76; H, 4.01; N, 124.50,125.38,128.01,129.84,137.38,140.93,143.46,147.09, 17.43. Found: C, 65.34; H, 4.17; N, 17.11. 5 4 (4-Chloro-3-ethoxyphenyl)aminol-1,2-dihydro-3,9-160.11; EIMS (70 eV), mlz (re1 inten) 431 (M+, 100); HRMS dimethyl-1-oxo-2-phenylpyrazolo[3',4':4,5lpyrido[6,l~l- calcd for C22H21N,03 mlz 431.1706, found 431.1711. Anal.

Synthesis of Zwitterionic Heteropolycyclic Pyrazoles

J . Org. Chem., Vol. 59, No.14, 1994 3993

Hz), 4.05 (4,2,J = 7.21 Hz), 7.4-7.6 (m,81,7.7 (d, 2,J = 7 Hz)9.8 ( 8 , 1);13CNMR (60.25MHz) (DMSO) 6 14.80,42.11, 104.46,122.21,122.86,126.70,127.93,128.825,128.96,129.13, 8-(4-Chlorophenyl)-~-ethyl-S-(phenylamino)-SH,7R-

Calcd for C&21N703: C, 61.24;H, 4.91;N,22.72. Found: C, 60.93;H, 4.42;N, 22.33.

pyrazolo[3,4-el[1,2,41triazolo[l~%-al~1,2,4ltriazine-7,9- 130.30,134.04,135.80,140.71,143.14,146.67;EIMS (70eV) mlz (re1 inten) 421 (M+, 100);HRMS calcd for CmHleClN702 (8H)dione(9b). As described above for compound 9a,4-chlomlz 421.1054, found 421.1053. Anal. Calcd for CzOH16rophenyl-TAD (500mg, 3 m o l ) and phenyl isocyanate (360 ClN70~:C, 56.95;H, 3.82;N, 23.24. Found: C, 56.77;H, 3.92; mg, 3 "01) were added to the iminophosphorane 2 (500 mg, N, 22.86. 1.3mmol). The crude residue was recrystallized from a small amount of warm ethyl acetate to give colorless needles: yield Acknowledgment. We thank the Deutsche For65 mg (12%), mp 229-230 "C;IR (KBr)3225,3080,2980,2925, schungsgemeinschaft, the Fonds der Chemischen Indu1765,1690cm-l; UV-vis (1,4-dioxane) A (log E) 339 (2.86),247 strie, and the Bayer AG for generous support. (3.47)nm; 'H N M R (250MHz) (DMSO)6 1.35 (t, 3,J = 7.25